Unique ion channels activated by both glutamate and voltage, NMDA receptors (NMDARs) play crucial roles in synapse formation, synaptic plasticity, learning, and memory. NMDARs have been associated with either the pathogenesis or the damage caused by several neurological disorders including schizophrenia, epilepsy, Parkinson's disease, drug addiction, and ischemia/stroke. The modulation of NMDARs by intracellular signaling pathways is an active area of investigation. Growing evidence now suggests that activity can dynamically regulate NMDARs, though much remains unexplored. We are currently aware of activity-dependent NMDAR regulation at only a few synapses, although its underlying molecular mechanisms and functional consequences remain unknown. We propose experiments to identify the mechanisms and specific functional contributions of activity-dependent NMDAR modulation, beginning with a novel form recently discovered in our laboratory. Recently we found that brief tetanic activity can induce long-term potentiation of NMDAR-mediated transmission at the hippocampal mossy fiber-CA3 pyramidal cell synapse (NMDAR-mfLTP). Preliminary data suggests that NMDAR-mfLTP is induced and expressed postsynaptically in a Ca2+-dependent process and is restricted to NMDARs. We propose to investigate the molecular mechanisms and functional consequences of NMDAR-mfLTP using electrophysiological recording and functional analysis, pharmacological manipulation, and Ca2+ imaging in acute hippocampal slices. In studies of the induction mechanism, we will use inhibitors and activators of signal transduction pathways including those known to regulate NMDARs in expression systems and cultured neurons. We will investigate whether this potentiation is expressed as an increase in NMDAR number and/or function. In terms of function consequences, we will determine whether NMDAR-mfLTP is associated with long-term enhancement of Ca2+ signaling at mf-CA3 synapses, and we will test the hypothesis that NMDAR-mfLTP will substantially modify the input/output function of this synapse. In addition, we will test whether NMDAR-mfLTP, once established, might modify the subsequent modifiability of excitatory and inhibitory CA3 synapses, a phenomenon known as metaplasticity. Finally, we will look for other forms of NMDAR plasticity at this synapse, including long-term depression, de-potentiation, and de-depression. Dynamic long-term modification of NMDARs may have important consequences for both normal and pathological physiology. For this reason, understanding the role of these forms of plasticity at the cellular and network level is critical to a more realistic representation of brain function, and may contribute to the development of therapeutic strategies to reverse or prevent NMDAR-mediated dysregulation or damage. PUBLIC HEALTH RELEVANCE: NMDA receptors are a subtype of receptors in the brain that participate in excitatory neurotransmission and are crucial for synapse formation, synaptic plasticity and learning and memory. Dynamic long-term modification of NMDA receptors by neuronal activity may have important consequences for both normal and pathological physiology with potential involvement in ischemia/stroke, epilepsy, schizophrenia, drug addiction, chronic pain, and Parkinson's disease. Understanding how these receptors are regulated is critical to a more realistic representation of brain function, and may contribute to the development of therapeutic strategies to reverse or prevent NMDAR-mediated dysregulation or brain damage.